R01AI189793

Chromatin architecture regulating trained immunity in antiviral NK cells - Project summary

Trained immunity is the process by which cells of the innate immune system gain a “memory” of previous infections.

Natural killer (NK) cells, innate lymphoid cells, macrophages are among the components of innate immunity where such training has been documented.

This R01 will attempt to better understand the molecular mechanisms that underlie trained immunity in NK cells.

NK cells protect us against viral infection, and because these cytotoxic lymphocytes are lacking in newborns and immunocompromised people (including cancer and transplant patients), these individuals are highly susceptible to viral infections, most prominently cytomegalovirus.

Trained immunity in NK cells can be studied using mouse cytomegalovirus (MCMV) infection, an accurate model of human disease, where we first demonstrated NK cells possess features of adaptive immunity, including antigen specificity, clonal expansion, and long-lived memory.

Over the years, my lab has uncovered many transcriptional and epigenetic mechanisms that control the adaptive NK cell response to MCMV infection.

This current R01 A1 resubmission will attempt to understand how the genomic 3D architecture impacts trained immunity in antiviral NK cells.

In exciting preliminary Hi-C and CUT&RUN data, we observe distinct patterns in the 3D genomic landscape, CTCF binding, and histone modifications as NK cells differentiate in response to MCMV.

To investigate how the 3D chromatin architecture controls trained immunity in NK cells during viral infection, we have generated new transgenic and knockout mice, along with novel sequencing techniques (for low numbers of primary lymphocytes) to be used in all 3 aims.

In Aim 1, we will test how chromatin organizers regulate 3D genomic landscape dynamics in NK cells during viral infection.

Aim 2 will identify transcription factors that control the genomic 3D architecture in MCMV-specific NK cells.

In Aim 3, we will determine the importance of putative enhancers and specific chromatin loops that regulate trained immunity in NK cells.

This R01 will enhance our understanding of the epigenetic mechanisms underlying NK cell responses, with the hopes of establishing innovative methods by which this potent cytotoxic lymphocyte can be targeted for treatment against infectious diseases and cancer.

Sloan-Kettering Institute For Cancer Research

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New York United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)